Because most potential molecular markers and targets are proteins, proteomic profiling is expected to yield more direct answers to functional and pharmacological questions than does transcriptional ...profiling. To aid in such studies, we have developed a protocol for making reverse-phase protein lysate microarrays with larger numbers of spots than previously feasible. Our first application of these arrays was to profiling of the 60 human cancer cell lines (NCI-60) used by the National Cancer Institute to screen compounds for anticancer activity. Each glass slide microarray included 648 lysate spots representing the NCI-60 cell lines plus controls, each at 10 two-fold serial dilutions to provide a wide dynamic range. Mouse monoclonal antibodies and the catalyzed signal amplification system were used for immunoquantitation. The signal levels from the >30,000 data points for our first 52 antibodies were analyzed by using P-Scan and a quantitative dose interpolation method. Clustered image maps revealed biologically interpretable patterns of protein expression. Among the principal early findings from these arrays were two promising pathological markers for distinguishing colon from ovarian adenocarcinomas. When we compared the patterns of protein expression with those we had obtained for the same genes at the mRNA level by using both cDNA and oligonucleotide arrays, a striking regularity appeared: cell-structure-related proteins almost invariably showed a high correlation between mRNA and protein levels across the NCI-60 cell lines, whereas non-cell-structure-related proteins showed poor correlation.
For analysis of multidrug resistance, a major barrier to effective cancer chemotherapy, we profiled mRNA expression of the 48 known human ABC transporters in 60 diverse cancer cell lines (the NCI-60) ...used by the National Cancer Institute to screen for anticancer activity. The use of real-time RT-PCR avoided artifacts commonly encountered with microarray technologies. By correlating the results with the growth inhibitory profiles of 1,429 candidate anticancer drugs tested against the cells, we identified which transporters are more likely than others to confer resistance to which agents. Unexpectedly, we also found and validated compounds whose activity is potentiated, rather than antagonized, by the MDR1 multidrug transporter. Such compounds may serve as leads for development.
Expert opinion remains divided on the issue of whether the hippocampal system functions exclusively in spatial information processing, e.g. in navigation or in understanding spatial relations, or ...whether it plays a more general role in higher brain function. Previous work on monkeys and rats has tended to support the former view, whereas observations in the clinic point to the latter, including functions as diverse as declarative knowledge, episodic memory, word learning, and understanding relations among objects. One influential theory posits a general role for the hippocampal system in associative learning, with emphasis on associations learned rapidly and recently. The results presented here are consistent with this theory, along with previous clinical and theoretical studies indicating that the hippocampal system is necessary for associative learning even if no component of the association relies on spatial information. In the study reported here, rhesus monkeys learned a series of conditional stimulus–response associations involving complex visual stimuli presented on a video monitor. Each stimulus instructed one of three responses: tapping the stimulus with the hand, steady hand contact with the stimulus for a brief period of time, or steady contact for a longer time. Fornix transection impaired the learning of these associations, even though both the stimuli and the responses were nonspatially differentiated, and this deficit persisted for at least 2 years. This finding indicates that the hippocampal system plays an important role in associative learning regardless of the relevance of spatial information to any aspect of the association. Fornix‐transected monkeys were impaired in learning new stimulus–response associations even when the stimuli were highly familiar. Thus, the deficit was one of associating each stimulus with a response, as opposed to problems in distinguishing the stimuli from each other. In contrast to these effects, fornix transection did not impair performance when familiar stimuli instructed a response according to an already‐learned association, which shows that the deficit was one of learning new associations rather than one of retention or retrieval of previously learned ones. Taken together, these results show that fornix transection causes a long‐lasting impairment in associative learning outside of the spatial domain, in a manner consistent with theories of hippocampal‐system function that stress a general role in the rapid acquisition of associative knowledge.
A
bstract
The exclusive photoproduction reactions
γp
→
J/ψ
(1
S
)
p
and
γp
→
ψ
(2
S
)
p
have been measured at an
ep
centre-of-mass energy of 318 GeV with the ZEUS detector at HERA using an integrated ...luminosity of 373 pb
−
1
. The measurement was made in the kinematic range 30
< W <
180 GeV,
Q
2
<
1 GeV
2
and |
t
|
<
1 GeV
2
, where
W
is the photon-proton centre-of-mass energy,
Q
2
is the photon virtuality and
t
is the squared four-momentum transfer at the proton vertex. The decay channels used were
J/ψ
(1
S
)
→ μ
+
μ
−
,
ψ
(2
S
)
→ μ
+
μ
−
and
ψ
(2
S
)
→ J/ψ
(1
S
)
π
+
π
−
with subsequent decay
J/ψ
(1
S
)
→ μ
+
μ
−
. The ratio of the production cross sections,
R
=
σ
ψ
(2
S
)
/σ
J/ψ
(1
S
)
, has been measured as a function of
W
and |
t
| and compared to previous data in photoproduction and deep inelastic scattering and with predictions of QCD-inspired models of exclusive vector-meson production, which are in reasonable agreement with the data.
The glutamate system has been strongly implicated in the pathophysiology of psychotic illnesses, including schizophrenia and schizoaffective disorder. We recently found that knockout (KO) mice ...lacking the AMPA GluA1 subunit displayed behavioral abnormalities relevant to some of the positive symptoms of these disorders. Here we phenotyped GluA1 KO mice for behavioral phenotypes pertinent to negative and cognitive/executive symptoms. GluA1 KO mice were tested for conspecific social interactions, the acquisition and extinction of an operant response for food-reward, operant-based pairwise visual discrimination and reversal learning, and impulsive choice in a delay-based cost/benefit decision-making T-maze task. Results showed that GluA1 KO mice engaged in less social interaction than wildtype (WT) controls when tested in a non-habituated, novel environment, but, conversely, displayed more social interaction in a well habituated, familiar environment. GluA1 KO mice were faster to acquire an operant stimulus-response for food reward than WT and were subsequently slower to extinguish the response. Genotypes showed similar pairwise discrimination learning and reversal, although GluA1 KO mice made fewer errors during early reversal. GluA1 KO mice also displayed increased impulsive choice, being less inclined to choose a delayed, larger reward when given a choice between this and a smaller, immediate reward, compared to WT mice. Finally, sucrose preference did not differ between genotypes. Collectively, these data add to the growing evidence that GluA1 KO mice display at least some phenotypic abnormalities mimicking those found in schizophrenia/schizoaffective disorder. Although these mice, like any other single mutant line, are unlikely to model the entire disease, they may nevertheless provide a useful tool for studying the role of GluA1 in certain aspects of the pathophysiology of major psychotic illness.
This article is part of a Special Issue entitled ‘Schizophrenia’.
The present study provides evidence that lesions of the fornix (FNX) and of the perirhinal/postrhinal cortex (PPRH), which both disconnect the hippocampus from other brain regions, can lead to ...distinct patterns of behavioural impairments on tests of spatial memory and spontaneous object recognition. For example, whereas FNX lesions impaired allocentric spatial delayed alternation in a T-maze but generally spared a test of spontaneous object recognition, PPRH lesions produced the opposite pattern of results. Indeed, on the T-maze task PPRH animals significantly outperformed controls when the retention delay was increased to 60 s. In addition, some evidence was found that contributions from both the fornix and perirhinal/postrhinal cortex may be required when object and spatial information must be integrated. In an object-in-place test, for example, PPRH animals failed according to two measures, and FNX animals failed according to one measure, to discriminate objects that had remained in fixed locations from those that had exchanged locations with other objects. Neither lesion, however, affected performance of a visuospatial conditional task, a Pavlovian autoshaping task, or a one-pair pattern discrimination task. It is suggested that the perirhinal/postrhinal cortex, rather than being specialised for a particular type of associative learning, is important for processing complex visual stimuli.
A summary is given of recent ATLAS results at the LHC, covering a number of areas that reflect the Collaboration's work in low energy physical observables in multiparticle events, elastic ...photon-photon scattering, proton-proton scattering and the tagging of diffractive events.
Reciprocal interactions between the hippocampus and the perirhinal and parahippocampal cortices form core components of a proposed temporal lobe memory system. For this reason, the involvement of the ...hippocampus in event memory is thought to depend on its connections with these cortical areas. Contrary to these predictions, we found that NMDA-induced lesions of the putative rat homologs of these cortical areas (perirhinal plus postrhinal cortices) did not impair performance on two allocentric spatial tasks highly sensitive to hippocampal dysfunction. Remarkably, for one of the tasks there was evidence of a facilitation of performance. The same cortical lesions did, however, disrupt spontaneous object recognition and object discrimination reversal learning but spared initial acquisition of the discrimination. This pattern of results reveals important dissociations between different aspects of memory within the temporal lobe. Furthermore, it shows that the perirhinal-postrhinal cortex is not a necessary route for spatial information reaching the hippocampus and that object familiarity-novelty detection depends on different neural substrates than do other aspects of event memory.
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